Affective Disorders
Brian J. Piper, Ph.D., M.S.
Goals
• Serotonin (5-HT)• Major Depressive Disorder• Bipolar Disorder
Major Depressive Disorder
• Five + (1 or 2) causing significant social or occupational impairment not due to medical condition– 1) Depressed mood most of the day, nearly every day– 2) Marked diminished interest or pleasure, in activities– 3) Significant weight loss/gain (+5%/month)– 4) Insomnia/hypersomnia– 5) Fatigue or loss of energy– 6) Diminished ability to think or concentrate– 7) recurrent thoughts of death, suicidal attempt/plan
Anna M. Kring, Ph.D. Lecture 14, 19:38-23:08
Edvard Munch (1863-1944)
Despair (1894)
Vincent van Gogh (1853-1890)
Sorrowing Old Man (‘At Eternity’s Gate’)1890
MDD
• Episode = 6 months• Female: Males (2:1)• Age of Onset (younger)
Heritability
BMJ 1999; 319 : 37
Biosynthesis
HO: hydroxylCOOH: carboxyl
Biosynthesis
Tryptophan: yogurt, milk, fish, nuts
Tryptophan hydroxylase: rate limitingstep
Role of 5-HT in MDD
• Methods: 15 un-medicated women with a history of 2+ episodes of depression were on a low protein diet for 1 week, then randomly assigned to receive:– Tryptophan + : L-tryptophan (1.9 g), L-alanine (4.6
g) L-arginine (4.1 g)
– Tryptophan - : L-alanine (4.6 g) L-arginine (4.1 g)
Hamilton Depression Inventory
http://www.psy-world.com/online_hamd.htm
Ham-D
http://www.psy-world.com/online_hamd.htm
Max Hamilton
1912-1988
Smith et al. (1997). Lancet, 349, 915-919.
Smith et al. (1997). Lancet, 349, 915-919.
5-HT & Aggression
• Para-chlorophenylalanine (PCPA): irreversible tryptophan hydroxylase inhibitor
• PCPA treated rats were tested for muricide
Killers Non-killers
Control 0 13
PCPA 14 4
Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.
5-HT & Aggression• muricide: mouse killing• PCPA: aggression• PCPA + 5-HTP: no
aggression
Paxinos et al. (1977). Pharmacology, Biochemistry, Behavior, 6, 439-447.
Serotonergic Projects
• Cell bodies in Raphe
• Projections throughout CNS
5-HT Functions
Spinal Cord Sexual dysfunction
Brain stem Nausea
Modified from Stahl (2001) p. 182
5-HT Functions
Limbic Anxiety
Brain stem Insomnia
Modified from Stahl (2001) p. 182
5-HT Functions
Frontal Cortex Mood
Hypothalamus Appetite (Bulimia?)
Modified from Stahl (2001) p. 182
Fenfluramine• Fenfluramine is a 5-HT releaser that was used
with phentermine for weight control• Animal studies indicate fenfluramine causes 5-HT
axotomy• Methods: Former fenfluramine users (N=15) and
controls (N=17) completed PET imaging
McCann et al. (2007). Molecular Imaging & Biology, 9, 151-157.
5-HT Receptors
Postsynaptic1A1B2A2C4567
Presynaptic1A
5-HT1A Agonist: 8-OH-DPAT
• Example#1: Rats received MDMA from age 35 to 60• A 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin)
challenge was administered at age 67
Piper et al. (2006) JPET, 317, 838-849.
5-HT2A Agonist: DOI
• Example #2: Rats received MDMA from age 35 to 60
• A DOI (di-methoxy-4-iodophenyl)-2-aminopropane) challenge was administered at age 67
Biezonski et al. (2009) Brain Research, 1252, 87-93.
MAO-Is
• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA
MAO-Is
• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA; peak use in 1970s
• Food Interactions: – Tyramine: amino acid breakdown product of
tyrosine, doesn’t cross BBB but causes norepinephrine release
– Tyramine rich foods (aged cheese, beer, wine) + MAO-I results in increased blood pressure & headaches (“cheese effect”)
MAO-Is
• Monoamine Oxidase (MAO) is an enzyme that breaks down 5-HT, NE, & DA
• Food Interactions: tyramine foods (aged cheese, beer, wine) results in increased norepinephrine (blood pressure)
• Drug Interactions: increased activity of drugs that elevated 5-HT, NE, DA (cocaine, hypericum, ritalin)
• 1st generation were irreversible inhibitors (1960s), 2nd generation are reversible inhibitors
Tricyclic Antidepressants
• Developed from antipsychotic drugs• Have 3 ringed structure
SERT & NET Blockade+
Serotonin Reuptake Inhibitors
• Prozac (fluoxetine) was the original SRI• Greater affinity for SERT than NET• Not Selective (sigma receptors, CYP2D6)• Anorgasmia
ComparisonMAO-Is TCA SSRIs
Efficacy Moderate Moderate Low
Side-effects “cheese effect”, many drug interactions
orthostatic hypertension, OD
Sexual, DiscontinuationSyndrome
Prevalence very low low high
Mechanism 5-HT, NE, DA 5-HT & NE 5-HT
Therapeutic Lag Yes Yes Yes
Other Mechanisms of Antidepressants
• 5-HT2
• Intracellelar (e.g. cAMP)• Brain Derived Neurotrophic Factor
Cortisol
• The Hypothalamus-Pituitary-Adrenal (HPA) axis control release of the stress hormone cortisol.
• As many as half of depressed patients show elevations in cortisol. Drugs that turn off the HPA axis are ineffective.
Belmaker & Agam (2008). New England Journal of Medicine, 358, 55-68.
Structural Changes following Elevated Cortisol?
• Rat research indicate that persistent increases in cortisol are toxic to hippocampal neurons.
• Studies examining the volume of the hippocampus in MDD were inconsistent.• A meta-analysis showed that the left (-4.5%) and right hippocampus (-4.0%)
showed reductions.
Cole et al. (2011). J of Affective Dis 134, 483-487.
Antidepressants & Neurogenesis
• New neurons are produced in the hippocampus in adults
ECS: electroconvulsive therapy; TCP: trancyclpromine (MAO-I), or Reboxetine (SNRI)
Mahlberg (2000). J Neurosciece, 20, 9104-9110.
Electroconvulsive Therapy
• The most effective treatment for MDD (especially high suicide risk)
• Controversial!• Potential memory loss• George, David T. (2011). Electroconvulsive therapy. Starts at
54:50: http://videocast.nih.gov/Summary.asp?File=16674
Cognitive Behavioral Therapy
• Short, evidence based, therapy• Developed by Aaron T. Beck• Instruction in how thoughts & feelings
influence behavior
1921-
CBT + Medication• Patients randomized to receive Nefazodone (5-
HT2A/1 antagonist), CBT, or both for 3 months
Nef CBT Nef +CBTCompleters 69.5% 72.2% 76.5%
No Response 44% 48% 15%Remission 22% 24% 42%
Keller et al (2000). New England J of Medicine, 342, 1462-1470.
Diagnosis of Bipolar
• Bipolar I: – manic episode– depression not
required– not due to
recreational drugs
• Bipolar II:– Hypomanic Episode– major depressive episode– not due to recreational
drugs
Example of Mania
• Lifetime prevalence: 1% • 1st Minute:
http://www.youtube.com/watch?v=rcl09ztmoDw
Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.
National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based visits by youth (aged 0-19 years) and adults (aged >= 20 years)
Bipolar Disorder
Many great writers, poets, and composers suffered from bipolar disorder.
During their manic phase creativity surged, but not during their depressed
phase.
Whitman Wolfe Clemens Hemingway
Bettm
ann/ Corbis
George C
. Beresford/ H
ulton Getty P
ictures Library
The G
ranger Collection
Earl T
heissen/ Hulton G
etty Pictures L
ibrary
Treatment
• Lithium carbonate (Li2CO3)• John Cade, Australian psychiatrist, on giving
lithium to guinea pigs:– “After a latent period of about two-hours, the animals, although fully conscious
became extremely lethargic and unresponsive to stimuli for one to two hours before once again becoming timid and active. Those who have experimented with guinea pigs know to what extent a ready startle reaction is part of their makeup. It was even more startling to find that after the injection of a solution of lithium carbonate they could be turned on their backs and that, instead of the usual frantic righting behavior, they merely lay there and gazed placidly back at him.”
Depression & Pregnancy
• Drug treatment & pregnancy is a tough decision.
• Depression may also occur Post-partum.
Payne, Jenifer L. (2011). Clinical care of Major Depression during pregnancy. Starts at 31:20: http://videocast.nih.gov/Summary.asp?File=16674
